Update in Diabetes Management Insulin Therapies

Amy M. Lugo, PharmD, BCPS, CDM Clinical Coordinator Department of Pharmacy National Naval Medical Center Bethesda, Maryland

Objectives

Review rationale for insulin therapy Describe cell functional decline Understand the advantages and disadvantages of insulin therapy Review insulin preparations and activity profiles Introduce newer therapies in the pipeline

Rationale for Insulin Therapy in Type 2 DM

Up to 1/3 of patients may require insulin to achieve adequate glycemic control The UKPDS Trial
Demonstrated progressive hyperglycemia Decrease in -cell function All treatment groups

Gerich JE. Am J Med 2002;113:308-316.

Beta-cell decline
Beta-cell Function (%) 100 80 60 40 20 0
0 2 4 -1 0 -8 -6 -4 -2 6

Years

Mudaliar S, et al. Endo and Metab Clin of NA 2001;03(4):935-982.

Indications for Insulin Therapy in Type 2 DM

Persistently elevated FPG > 300 mg/dL and ketonuria or ketonemia Persistent elevations of FPG > 300 mg/dL and sx of polyuria, polydipsia, and weight loss All women with gestational diabetes whose disease is not controlled with diet alone and women with Type 2 DM who become pregnant

Insulin Preparations

Lispro/Aspart/Glulisine
Humalog , NovoLog, Apidra

Human Regular
Humulin R , Novolin R

Human NPH/Lente
Humulin N, Novolin N Humulin L , Novolin L

Ultralente
Humulin U

Glargine
Lantus

Activity Profiles
Preparation Rapid-acting Insulin lipsro Insulin aspart Short-acting Regular insulin Intermediate-acting Isophane (NPH) insulin Insulin zinc (Lente) Long-acting Insulin zinc (Ultralente) Insulin glargine Mixtures Isophane/regular insulin 70/30, 50/50 NPL/lispro Mix 75/25 Onset 15 minutes 15 minutes 30 minutes 1-2 hours 1-2 hours 4-6 hours 2 hours 45 minutes 5 minutes Peak 30-60 minutes 30-60 minutes 2-5 hours 6-10 hours 6-12 hours 10-18 hours None 7-12 hours 7-12 hours Duration 3 hours 3 hours 5-8 hours 16-20 hours 18-24 hours 24-48 hours > 24 hours 16-24 hours 1-24 hours

NPH = neutral protamine Hagedorn; NPL = neutral protamine lispro

Campbell RK, et al. J Am Pharm Assoc 2002;42:602-11.

Novel Insulins

Novel Bolus Insulins

Insulin lispro Insulin aspart Inhaled insulin

Novel Basal Insulins

Insulin glargine Fatty acid acylated insulins
Insulin detemir
Gerich JE. Am J Med. 2002;113:308-316.

A-CHAIN 1 5 10

Insulin Lispro
15 20 5 10 15 25
Lys Pro 30

1 B-CHAIN A-CHAIN 1

Inversion

Insulin Aspart
5 10 15 20 5 10 15 20 25 30 Asp

1 B-CHAIN

Substitution
A-CHAIN 1 5

Insulin Glargine
10 15 20 5 10 15 20

Gly

1 B-CHAIN

25

30

Extension

Arg Arg

Insulin Lispro (Humalog)

Advantages
Improved glycemic control in patients with Type 1 DM who inject insulin immediately before meals Subcutaneous absorption characteristics and plasma profile more closely resembling mealstimulated physiologic insulin release More flexible lifestyle from immediate preprandial dosing schedule Rapid-acting insulin Ability to administer a few minutes before meals

Insulin Aspart (NovoLog)

Advantages
Absorption more than twice as fast, peak levels more than twice as high, as with regular insulin Improved glycemic control in patients with Type 1 DM injecting insulin immediately before meals (in conjunction with regular basal insulin)

Insulin Lispro/Aspart

Disadvantages
More rapid onset of ketoacidosis in cases of continuous subcutaneous insulin infusion pump failure Unknown teratogenicity and long-term safety profile Higher cost Need for one to two more daily insulin injections

Insulin Glargine (Lantus)

Long-acting, peakless insulin Administered once daily Lower risk of nocturnal hypoglycemia Less weight gain compared with NPH Often used in combination with other insulins, oral agents, or possibly inhaled insulin

Newer Therapies

Insulin glulisine (Apidra) Insulin detemir (Levemir) Inhaled insulin (Exubera) Pramilintide acetate (Symlin) Exenatide (Byetta) Sitagliptin (Januvia)

Insulin glulisine (Apidra)

Class: Rapid-acting insulin Indication

Bolus insulin designed for meal-time coverage of blood sugars in Type 1 or 2 DM

Administration
Injected subcutaneously 15 minutes before or after a meal

Adverse effects
Hypoglycemia, injection site reactions, lipodystrophy, pruritis, rash

A-CHAIN 1 5 10

Insulin Glulisine
15 20 5 10 15 25
Lys Pro 30

1 B-CHAIN A-CHAIN 1

Inversion

Insulin Aspart
5 10 15 20 5 10 15 20 25 30 Asp

1 B-CHAIN

Substitution
A-CHAIN 1 5

Insulin Glargine
10 15 20 5 10 15 20

Gly

1 B-CHAIN

25

30

Extension

Arg Arg

Insulin detemir (Levemir)

Class: Long-acting insulin Indication

Basal insulin designed for meal-time coverage of blood sugars in Type 1 or 2 DM

Administration
Injected SQ once or twice daily every evening or hs Should not be mixed with other insulins

Insulin detemir (Levemir)

Dose
Start with a 1:1 ratio from a basal insulin Can be given q12 hours Some pts may need higher doses of Levemir than NPH Insulin nave pts with poor control on PO drugs: 0.1-0.2 units/kg once daily in evening or 10 units once/twice daily

Adverse effects
Hypoglycemia, injection site reactions, lipodystrophy, pruritis, rash

Insulin detemir (Levemir)

Advantage
Less burning on injection Cheaper than Lantus

Inhaled Insulin (ExuberaTM)

Insulin human [rDNA origin] inhalation powder Rapid-acting, dry-powder insulin Should be given within 10 minutes before a meal Side Effects: hypoglycemia, cough, dry mouth, chest discomfort Not recommended for those with a chronic lung disease (asthma, COPD)

Inhaled Insulin (ExuberaTM)

Advantages
Reaches peak level more than twice as fast as insulin delivered via subcutaneous injections Offers more flexible lifestyle through immediate pre-meal administration Resembles meal-stimulated physiologic insulin release more closely Reduces duration of postprandial increases in blood glucose levels May be linked to less weight gain Eliminates need for preprandial injections

Inhaled Insulin (ExuberaTM)

Disadvantages
Requires much higher insulin doses because of limited penetration to the alveoli Higher cost Permits less precise dose calibration because of 1-mg and 3-mg minimum dose increments

Pramlintide (Symlin)

Class: Amylin agonists Indication: Patients with Type 1 or 2 DM uncontrolled on QID insulin therapy MOA

Synthetic analog of human amylin Naturally occurring hormone made in pancreatic beta cells Reduction of postprandial glucagon secretion Regulation of gastric emptying, and therefore the rate of nutrient delivery (exogenous glucose) to the small intestine

Pramlintide (Symlin)

Administration
Given SQ 15 minutes prior to meals Do not mix with other insulins Patient must give multiple injections at separate times

Caution: Initially decrease insulin doses by 50% to avoid hypoglycemia Medication Error Risk!!

Doses available in 15, 30, 60, and 90mcg doses Patient must draw up dose in unit syringes

Cost Comparison
Drug
Apidra Humalog Novolog Humulin R Humulin N ExuberaTM Kit ExuberaTM ByettaTM Symlin

Vial
10ml 10ml 10ml 10ml 10ml Starter kit Pack - #270 250mcg/ml Pen 0.6mg/5ml

Cost
$45.39 $46.33 $25.19 $11.33 $11.33 $109.17 $101.86 $108.78 $57.85

The Incretin System

Incretin hormones
Glucose-dependent insulinotropic polypeptide (GIP) Glucagon-like peptide-1 (GLP-1)

Eating causes secretion of hormones the GI tract Enzyme G-protein-coupled receptors (GPCRs)

from

Dipeptidyl peptidase-4 (DPP-4) inactivates GLP-1

Lancet 2006;368:1696-705.

The Incretin System

Actions of GLP-1
Inhibits glucagon secretion Inhibits gastric emptying Inhibits food ingestion Promotes glucose disposal GLP-1 receptors (GLP-1R) are expressed in islet and cells and in peripheral tissues
Lancet 2006;368:1696-705.

Exenatide (ByettaTM)

Class
Incretin mimetics GLP-1R agonists

Indication

Adjunctive therapy in patients with Type 2 diabetes uncontrolled on metformin, a sulfonylurea, or their combination

Do not need to be on insulin therapy

Exenatide (ByettaTM)

MOA

Mimics the effects of the incretin glucagon-like peptide 1 (GLP-1) Enhances glucose-dependent insulin secretion by pancreatic beta-cells Suppresses inappropriately elevated glucagon secretion Slows gastric emptying SQ injections in pre-filled pens

Administration Major adverse effect: nausea

Sitagliptin (Januvia)

Class
Dipeptidyl peptidase-4 inhibitor (DPP-4)

Indication
Treatment of DM2 Monotherapy and as add-on therapy to metformin or thiazolidinediones (TZDs) NOT approved with insulin or sulfonylureas

Dose: 100 mg once daily

Sitagliptin (Januvia)

MOA
Enhances the incretin system by inhibiting DPP-4, which breaks down GLP-1 Helps to regulate glucose by affecting beta cells and alpha cells

Adverse effects
( 5%) stuffy or runny nose, sore throat, URI, and headache

Sitagliptin (Januvia)

Advantages
Does not cause weight gain Less GI side effects

Safety concerns
May effect other endogenous hormones No long-term studies published 52 week ongoing study of patients inadequately controlled on metformin monotherapy
Pts randomized to either sitagliptin 100mg qd plus metformin or glipizide plus metformin Abstract suggested only HbA1c %0.67 decrease
Diabetes Care 2006. 29(12):2632-2637.

On the Horizon

GLP-1R Agonists
Liraglutide Novo Nordisk

DPP-4 inhibitors
Vildagliptin (Galvus) Novartis Saxagliptin Denagliptin

Lancet 2006;368:1696-705.

Summary

Diabetes affects a major percentage of the US population Screening of at-risk patients early on is essential to delay or prevent DM from developing Treat the whole patient, not just their DM More options on the horizon for controlling blood sugars, but be wary